Efficacy of sacituzumab govitecan (anti-Trop-2-SN-38 antibody-drug conjugate) for treatment-refractory hormone-receptor positive (HR+)/HER2- metastatic breast cancer (mBC).

Bardia, Aditya; Diamond, Jennifer R.; Vahdat, Linda T.; Tolaney, Sara M.; O’Shaughnessy, Joyce; Moroose, Rebecca; Mayer, Ingrid A.; Abramson, Vandana G.; Juric, Dejan; Sharkey, Robert M.; Washkowitz, Sarah A.; Wegener, William A.; Goldenberg, David M.; Kalinsky, Kevin

doi:10.1200/jco.2018.36.15_suppl.1004

Cited by 19 publications

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“…Results from the phase II dose expansion portion identified the 10 mg/kg dose for further evaluation 20 . Findings from the individual cohorts from the phase I/II basket study including breast, urothelial, non-small cell and small cell lung cancer patients showed overall response rates ranging from 14% to 33% [9][10][11][12][13] . In the cohort of 108 patients with triple negative breast cancer, who had received at least 2 prior lines of chemotherapy (median 3, range 2-10), the response rate (3 complete and 33 partial responses) was 33.3% (95% confidence interval [CI], 24.6 to 43.1), and the median duration of response was 7.7 months (95% CI, 4.9 to 10.8) 9 .…”

Section: Discussionmentioning

confidence: 99%

“…Low expression levels in normal healthy tissues make Trop-2 a suitable target for ADCs in cancer treatment 8 . Sacituzumab govitecan has shown promising activity in a recent phase I/II trial including patients with triple negative breast cancer 9 , hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer 10 , urothelial cancer 11 , small cell 12 and non-small cell lung cancers 13 . Several registrational clinical trials are also underway in patients with metastatic urothelial cancer (TROPHY U-01; NCT03547973), triple-negative breast cancer (ASCENT; NCT02574455), and HR + /HER2-breast cancer (TROPICS-02; NCT03901339)…”

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confidence: 99%

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Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan

Zeybek

Manzano

Bianchi

et al. 2020

Sci Rep

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Human trophoblast cell-surface marker (Trop-2) is a surface glycoprotein originally identified in human placental tissue and subsequently found to be highly expressed by various types of human epithelial solid tumors. We investigated the efficacy of sacituzumab govitecan, an antibody-drug conjugate (ADC) comprised of a humanized anti-Trop-2 antibody, conjugated with active metabolite of irinotecan (SN-38), on Trop-2 positive cervical cancer cell lines and a xenograft model. Trop-2 expression was evaluated in 147 primary cervical tumors by immunohistochemistry, real-time polymerase chain reaction, and flow cytometry. For in vitro experiments, two Trop-2 positive (CVX-8, ADX-3), and one Trop-2 negative (ADX-2) cell lines were used. A cell line with a strong Trop-2 expression (CVX-8) was used to test in vivo antitumor activity in xenografts models. Out of 147 primary cervical cancers, 113 were squamous cell carcinomas (SCCs), and 34 were adenocarcinoma/adenosquamous carcinomas. Moderate to strong diffuse staining was seen in 95% (108/113) of SCCs, and 81% (29/34) of adenocarcinoma/ adenosquamous cancers on immunohistochemistry. Trop-2 positive cell lines were highly sensitive to sacituzumab govitecan in vitro, with ic 50 values in the range of 0.18 to 0.26 nM (p = 0.02, and p = 0.04 for CVX-8, and ADX-3, respectively). In xenografts, a significant tumor growth inhibition was seen after twice-weekly intravenous administration of the drug for three weeks (p < 0.0001, and p = 0.001 for sacituzumab govitecan vs naked antibody, and sacituzumab govitecan vs control-ADC, respectively). Overall survival at 90 days was significantly improved in the sacituzumab govitecan group (p = 0.014). in conclusion, sacituzumab govitecan may represent a novel targeted therapy option in cervical cancer patients overexpressing Trop-2. Recent advances in treatment of cancer have not had a major impact in cervical cancer. It is the fourth most frequent cancer in women across the world after breast, colorectal, and lung with estimated 569,847 new cases and 311,365 deaths annually 1. In 2019, it is estimated that there will be 13,170 new cases in the US and an estimated 4,250 people will die of this disease 2. The frontline therapy after initial diagnosis is either surgery or a combination of chemotherapy and radiation depending on the stage and the patient factors 3. Although the overall 5-year

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan

Zeybek

Manzano

Bianchi

et al. 2020

Sci Rep

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“…Initial recent results in a study of 54 advanced patients with heavily-pretreated hormone-positive, HER2-negative, metastatic breast cancer have disclosed an encouraging 31% objective response rate [ 135 ].…”

Section: Antibody-drug Conjugates (Adcs)mentioning

confidence: 99%

“…Clinically, the first indication for this ADC is expected to be advanced TNBC [ 106 , 107 ], but encouraging clinical results have also been reported in NSCLC, SCLC, and UC [ 102 – 105 ], as well as more recently in metastatic hormone-positive metastatic breast cancer [ 135 ]. Early and preliminary studies also suggest that TROP-2 may be a suitable target for immunotherapy.…”

Section: Perspectives and Conclusionmentioning

confidence: 99%

The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target

2018

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TROP-2 is a glycoprotein first described as a surface marker of trophoblast cells, but subsequently shown to be increased in many solid cancers, with lower expression in certain normal tissues. It regulates cancer growth, invasion and spread by several signaling pathways, and has a role in stem cell biology and other diseases. This review summarizes TROP-2's properties, especially in cancer, and particularly its role as a target for antibody-drug conjugates (ADC) or immunotherapy. When the irinotecan metabolite, SN-38, is conjugated to a humanized anti-TROP-2 antibody (sacituzumab govitecan), it shows potent broad anticancer activity in human cancer xenografts and in patients with advanced triple-negative breast, non-small cell and small-cell lung, as well as urothelial cancers.

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“…Bardia et al studied sacituzumab-govitecan in metastatic hormone receptor-positive/HER2-negative breast cancer that had proved resistant to at least one or more prior treatments and was progressive (NCT01631552) 44 . The conjugate consists of SN-38, the active metabolite of the cytostatic irinotecan, conjugated with a humanised monoclonal antibody against TROP2 (trophoblast cell-surface antigen 2) The patients received sacituzumab-govitecan at a dose of 10 mg/kg on days 1 and 8 of a 21-day cycle until progression or unacceptable toxicity 44 A total of 54 patients with an average age of 54 years were treated between February 2015 and June 2017. Most patients had undergone at least two previous anti-hormonal treatments with CDK4/6 inhibitors and/or cytostatic drugs.…”

Section: Advanced Breast Cancer – Antibody-drug Conjugatesmentioning

confidence: 99%

Update Breast Cancer 2018 (Part 4) – Genomics, Individualized Medicine and Immune Therapies – in the Middle of a New Era: Treatment Strategies for Advanced Breast Cancer

Müller

Wöckel

Lux

et al. 2018

Geburtshilfe Frauenheilkd

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New therapeutic developments aimed at treating women with advanced breast cancer currently focus both on identifying patients eligible for targeted therapeutic concepts and on the continuing development of immune therapies. The data on CDK4/6 inhibitors are now complete and consistent in this class of substances (palbociclib, ribociclib and abemaciclib). Further pathways under investigation are PI3K and AKT signalling pathways along with diverse approaches to their inhibition. Initial study results were also presented recently on both mechanisms of action. Insights into the PARP inhibitors, moreover, are increasing; studies in this respect are also examining in which population they can be used most effectively. This review offers a summary of the recent studies and an outline of the latest developments.

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Efficacy of sacituzumab govitecan (anti-Trop-2-SN-38 antibody-drug conjugate) for treatment-refractory hormone-receptor positive (HR+)/HER2- metastatic breast cancer (mBC).

Cited by 19 publications

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Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan

Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan

The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target

Update Breast Cancer 2018 (Part 4) – Genomics, Individualized Medicine and Immune Therapies – in the Middle of a New Era: Treatment Strategies for Advanced Breast Cancer

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